This application is related to Merck case 18727, U.S. Ser. No. 07/880,119, filed May 7, 1992, and to its continuation-in-part, Merck case 18727IA, U.S. Ser. No. 07/991,164, filed Dec. 16, 1992.
This invention relates to an improved process for synthesizing the AIDS antiviral L-738,372, which is a chiral compound having novel requirements in the crystallization step(s) of its improved synthesis.
The substituted quinazoline L-738,372 is an exceptionally potent inhibitor of HIV reverse transcriptase. This activity of the compound makes it useful in the treatment or prevention of AIDS. The present invention describes an improved synthesis of this compound.
Separating the enantiomers of the asymmetric carbon at position 4 is the penultimate or final step in the synthesis of the compound. Previous attempts use derivatization in lower yield, e.g., reaction with 1(S)-camphanic chloride as illustrated in Example 7. The disadvantages of camphanyl derivatization include the expense of the reagent, the need for two equivalents in the reaction, a chromatographic step to separate the non-crystalline diastereomeric derivatives, as well as a two step removal of the camphanate groups. In contrast, the advantages of the present method include the formation of a salt instead of a derivative, and substantially higher yields. Further, the present method is practical and amenable to scale up.
It is commonly known that crystallization is an unpredictable science. In this application, a novel and unexpected process of chiral resolution of the substituted quinazoline is achieved by a series of crystallizations.